tbuckley/cabot-search huggingface dataset:
Risk of seizures in a population of women with BRCA-positive metastatic breast cancer in the United States.
Authors: Wendy Sebby, Ryan Kilpatrick, Debasish Mazumder, Anirban Ghosh, Eros Papademetriou, Ravi Potluri, Alexander Liede
Journal: Journal of Clinical Oncology (2022)

e13056 Background: Real-world evidence on the risk of seizures in subgroups of women with advanced breast cancer (BC) across treatment-related or clinical subtypes is limited. A large electronic health record (EHR) dataset was used in this study to measure incidence and risk factors for seizures among women diagnosed with BRCA-associated metastatic BC (mBC). Methods: We used the Optum EHR database, which includes natural language processing (NLP) abstracted details from physicians’ notes, to identify a cohort of females with mBC (based on secondary malignancy ICD-9/-10 codes or NLP) diagnosed between 2008-2018 with 12 months of pre-index history, evidence of BRCA mutation positive (BRCA+) status, and no history of prior cancers. Analyses were stratified by the overall BRCA+ cohort and 4 molecular phenotypes: HER2+/HR-, HER2-/HR+, HER2+/HR+, and triple negative BC (TNBC). Incidence of seizures was measured using diagnosis codes and NLP, and incidence rates were calculated as the number of women with a seizure over the period from metastasis to first seizure or the end of follow up. Incidence rates were also measured across the following risk factors: PARP inhibitor use, diagnosed brain metastases, history of seizures, and anticonvulsant use before BC diagnosis, while controlling for age at metastasis, number of prior lines, and metastasis location. Results: Of the 7,941 BRCA+ patients identified, 27.8% had ≥1 seizure during mean follow-up of 2.35 years, with an incidence rate of 11.83 (95% CI: 11.35-12.33) per 100 person-years. The HER2-/HR+ and TNBC subgroups had the lowest and highest seizure incidence rates, respectively (10.94 [95% CI: 10.23-11.71] and 16.83 [95% CI: 15.34-18.46]). Kaplan-Meier analysis of time to seizure showed that HR- phenotype was associated with a longer time to first seizure. Patients with diagnosed brain metastases or a history of seizures had higher seizure incidence rates compared to patients without the respective risk factors (42.55 [95% CI: 28.59-63.30] vs 5.26 [4.20-6.59] and 34.76 [23.24-52.01] vs 6.35 [5.11-7.88]). Incidence trended higher with PARP inhibitor use, but patient numbers were low. Conclusions: Using both diagnosis codes and NLP, this study shows that seizures occur frequently in women with BRCA+ mBC, even those without diagnosed brain metastases. The seizure incidence rates by phenotype underscore their relevance when assessing seizure risk. These findings may have implications for clinical practice and for assessing benefit-risk ratios of novel agents.[Table: see text]
LGG-61. Cerebrospinal fluid as a source for liquid biopsy in pediatric gliomas
Authors: Liana Nobre, Monique Johnson, Robert Siddaway, Javal Sheth, Scott Ryall, Michelle Ku, Rodney Lyn, Ana Stucklin, Michal Zapotocky, Uri Tabori, Cynthia Hawkins
Journal: Neuro-Oncology (2022)

Abstract Central nervous system neoplasms are currently the leading cause of morbidity and mortality among childhood cancers, gliomas account for 50% of these cases. The last decade has seen a massive growth in our understanding of the genetic underpinnings of these cancers, including the discovery of multiple diagnostic, prognostic and therapeutic markers. However, molecular characterization of these tumours requires a biopsy, with no added therapeutic benefit particularly in unresectable tumors. Liquid biopsy is a minimally-invasive alternative to biopsies which enables molecular characterization to diagnose, monitor response to therapy, and potentially predict progression/recurrence. We here present the results of a customized capture based NGS panel including 21 commonly altered genes present in pediatric and AYA gliomas coupled with low pass whole genome as a diagnostic and monitoring liquid biopsy tool. To assess for common fusions, exonic and intronic regions of specific genes are covered to capture different breakpoints. To establish the sensitivity and specificity of this assay we have used a commercially available control (SeraseqR) with 18 known mutated genes of interest and a in house control sample with two additional mutations. Samples with low ctDNA concentration (10 ng) and a limit of detection as low as 0.5% variant allele frequency, had a sensitivity of 83% and specificity of 100%. At higher concentrations (30 ng of ctDNA) we achieved a sensitivity and specificity of 100 %. We are currently finalizing the validation steps ctDNA samples extracted from CSF collected intra-surgically, through ventricular shunt or lumbar puncture. Twenty-two samples have been tested with additional 40 samples in processing. Driver alterations were identified in 16/22 samples, with additional 3/4 samples having concordant CNV alterations between tumor and CSF. This work supports further implementation of CSF use as a minimal invasive source of diagnostic and monitoring sample in children and adolescent patients with gliomas.
RARE-29. Transcriptome characterization of pediatric adamantinomatous craniopharyngioma at the cellular level
Authors: Eric Prince, Tammy Trudeau, Oscar Chatain, Susan Staulcup, Juan Pedro Martinez-Barbera, Carsten Goerg, Todd Hankinson
Journal: Neuro-Oncology (2022)

Abstract BACKGROUND: Adamantinomatous Craniopharyngioma (ACP) is a neurologically devastating brain tumor that affects children and adults. It is histologically heterogeneous with epithelial populations that are characterized by the nuclear accumulation of mutated β-catenin, and activated Wnt signaling. Current models suggest that ACP growth is driven through paracine mechanisms characterized by the senescence-associated secretory phenotype (SASP). However, detailed pathogenic mechanisms remain unknown. Improved definition of the various cellular phenotypes that compose ACP will inform and advance our understanding of this disease. METHODS: Single cell RNA-sequencing (scRNA-seq) and multiplex ELISA were performed on pediatric ACP tissue and cyst fluid, respectively. Reference scRNA-seq data was obtained from PanglaoDB. Preprocessing and standard analyses were conducted using Seurat software. Cellular phenotypes were annotated using the Human Primary Cell atlas. Differential expression and functional enrichment analyses were utilized to identify Wnt-signaling activation and epithelial subpopulations. Paracrine signaling was inferred via CellChatDB. SASP Atlas was utilized to query marker gene lists. Pseudotemporal ordering was performed using monocle3. RESULTS: ACP tissue is heterogenous and contains multiple distinct immune signatures. ACP tissue contains 2 unique epithelial subpopulations, which demonstrate canonical Wnt-signaling and SASP, respectively. Pseudotemporal ordering suggests the initial oncogenic event to be of epidermal character, with subsequent aggressive behavior from a separate epithelial cell population. CONCLUSIONS: Based on gene expression, cell populations that correspond to the histologically identifiable epithelial whorls and palisading epithelium can be identified. These subpopulations display unique functional signatures. Simultaneous and synergistic therapeutic targeting of these separate epithelial populations may lead to improved patient care.
Targetable genomic mutations in young women with advanced breast cancer.
Authors: Norin Ansari, Lucy Gao, Ethan Sokol, Smruthy Sivakumar, Richard S.P. Huang, Maureen Pelletier, Mia Alyce Levy, Dean C. Pavlick, Natalie Danziger, Jeffrey S. Ross, Maryam B. Lustberg, Mariya Rozenblit
Journal: Journal of Clinical Oncology (2022)

1027 Background: Advanced breast cancer in women &lt; 40 years is more aggressive, with worse prognosis and disease-free survival, compared to older women with the disease. With increasing availability of targeted and immune therapies, we aimed to compare genomic alterations (GA) using comprehensive genomic profiling (CGP) of tumor tissue. Methods: We analyzed 2,049 breast cancers submitted to Foundation Medicine for CGP. Hybrid-capture based CGP was performed to evaluate all classes of GA. Tumor mutational burden (TMB) was determined on at least 0.8 Mbp of sequenced DNA and microsatellite instability was determined on at least 95 loci. Tumor cell PD-L1 expression (defined as tumor proportion score &gt;/= 1) was determined by IHC (Dako 22C3). We identified 28 (1.37%) patients &lt;30 years, 159 (7.76%) between 30-39 years, and 1862 (90.87%) &gt;/= 40 years. Breast tissue was used for CGP in 69.5% of cases and remainder of specimens were lymph node, metastatic, or unspecified. Results: Breast tumors were less likely to be estrogen receptor positive in younger women (54% of those &lt;30 years, 60% of those 30-39 years, 69.4% of those &gt;/= 40 years) and more likely to be triple negative (43%, 33%, 26.1% in the same respective groups). There was no clear pattern in HER2+ status by age (0%, 15.1%, 7.2%). Younger women had higher rates of BRCA1 (17.9%, 10.1%, 2.6%), BRCA2 mutations (7.10%, 5.70%, 4.1%), and RB1 mutations (14.3%, 9.4%, 6.1%), and lower rates of CDH1 (7.1%, 5%, 15.4%) and PIK3CA mutations (17.9%, 17.6%, 40.0%). Younger women were more likely to have PD-L1 expression (55.6%, 54.4%, 51.5%) but had lower frequencies of TMB &gt;10 (0.0%, 5.0%, 8.7%). Differences are statistically significant in BRCA1, CDH1, and PIK3CA. Conclusions: These findings confirm that young women with breast cancer have actionable GA. Different mutational profiles may support differential use of targeted and immune therapies. Statistically and clinically significant differences include higher BRCA1 mutations which may lend to PARP inhibitor use and lower PIK3CA mutations which may reduce alpelisib use. Higher RB1 mutations and immunotherapy biomarker differences were not statistically significant. However, these may clinically translate into CDK4/6 resistance and reduced immunotherapy options, respectively. [Table: see text]
EPID-07. Outcome disparities in children, adolescents and young adults with medulloblastoma: A population-based analysis
Authors: Isabel Genecin, Dottington Fullwood, Hanna Moisander-Joyce, Oscar Padilla, Hanna Minns, James Garvin, Luca Szalontay, Cheng-Chia Wu, Justine Kahn, Robyn D Gartrell
Journal: Neuro-Oncology (2022)

Abstract Medulloblastoma (MB) is the most common high-grade primary pediatric brain tumor. Recent registry-based studies in children with central nervous system (CNS) tumors have demonstrated that survival outcomes differ by race/ethnicity in multivariable analyses, with Hispanic patients having highest hazard of death overall. To investigate this finding in MB patients, we examined survival in children (0-14 years) and adolescent/young adults (15-39 years) with MB from 2007-2016 in the 2018 Surveillance Epidemiology and End Results Program database, using Kaplan Meier analysis, log-rank test and Cox proportional hazard ratios (HR) with 95% confidence intervals (CI). Race and ethnicity were categorized according to the U.S. Census, with Hispanic ethnicity (yes/no) analyzed separately from race (Black, White, Asian, Other). Among 1612 patients, 81% were White, 9% were Black, 8% were Asian or Pacific Islander, and 2% were from “other” or unknown racial groups. 28% of the cohort was of Hispanic ethnicity. Univariate analysis found that Black patients had a significantly higher hazard of death than White patients (HR=1.55, CI: 1.16 – 2.08, p=0.003). In contrast, Hispanic ethnicity was not significantly associated with outcome (HR=0.98, CI: 0.79-1.21, p=0.8). Medicaid or no insurance (vs. private) were each significantly associated with higher risk of death; Medicaid (HR =1.23, CI = 1.01 - 1.51, p=0.041); Uninsured (HR=2.07, CI=1.41-3.02, p=&amp;lt;0.001). Of the treatment modalities analyzed, patients who received neither chemotherapy nor radiation experienced higher hazard of death than patients who received both treatments (HR=3.63, CI 2.78-4.76, p=&amp;lt;0.001). Consistent with observations in other cancers, racial disparities are observed in patients with MB, with Black race conferring increased risk of death. Public insurance was also significantly associated with death, as was not receiving combined-modality therapy. Further work is needed to understand the multilevel factors impacting diagnosis, treatment and outcome among children and AYAs with MB and prospective studies are warranted.
Hospital rating websites play a minor role in hospital choice of uro-oncologic patients in Germany: Results of the multicentric NAVIGATOR-study
Authors: C. Groeben, K. Boehm, U. Sonntag, T. Nestler, J. Struck, M. Heck, M. Baunacke, A. Uhlig, M. Koelker, C.P. Meyer, B. Becker, J. Salem, J. Huber, M. Leitsmann, None Struck
Journal: European Urology (2022)
Are we overtreating stage I triple negative breast cancer in Ontario? A population-based study using the ICES database.
Authors: Kathryn Shum, Abdulkadir Hussein, Caroline M. Hamm
Journal: Journal of Clinical Oncology (2022)

e12511 Background: Triple-negative breast cancer (TNBC) has been associated with poorer long-term outcomes compared to other breast cancer subtypes. Due to the lack of targeted therapies, the use of adjuvant chemotherapy is the mainstay of treatment, and its efficacy has demonstrated to be correlated with tumor size. Currently, different national guidelines exist regarding chemotherapy in early stage I TNBC. This study aims to examine the outcomes of the use of adjuvant chemotherapy in stage I TNBC stratified by tumor size and treated in Ontario, using the ICES database. Methods: Records of stage I TNBC patients diagnosed in 2012 to 2014 were collected from the ICES database and analysed. Kaplan-Meier curves and log-rank tests were used to compared differences in overall survival (OS) between groups. Stage I TNBC cancer patients were analyzed by tumor size: T1a (&lt; 0.5 cm), T1b (&gt; 0.5 cm and &lt; 1.0 cm) and T1c (&gt;1.0 cm and &lt; 2.0 cm). A Cox proportional hazard model was used to determine significance of variables. Results: Of the 610 stage I TNBC patients, 183 had tumor sizes ≤ 1cm, representing stages T1aN0M0 and T1bN0M0, and 427 had tumor sizes &gt; 1cm to 2cm, representing stage T1cN0M0. Patients with tumor sizes ≤ 1cm who received adjuvant chemotherapy did not have a significant difference in OS compared to those who did not receive adjuvant chemotherapy (p = 0.41, hazard ratio (HR) = 0.40, 95% confidence interval (CI) 0.021-2.5). However, patients with tumor sizes &gt; 1cm to 2cm who received adjuvant chemotherapy demonstrated a significantly better OS compared to those without (p = 0.023, HR = 0.40, 95% CI 0.16-0.86). Conclusions: Patients with TNBC stage T1cN0M0 should receive adjuvant chemotherapy for better OS. For stages T1aN0M0 and T1bN0M0, patients may be overtreated and avoidance of adjuvant chemotherapy can be considered at this time. Prospective studies should investigate the efficacy of adjuvant chemotherapy in TNBC patients with stage T1aN0M0 and T1bN0M0.
Bilateral Complete Ophthalmoplegia in a 50-Year-Old Man
Authors: Nitika Arora, Jacqueline Leavitt, John J. Chen
Journal: JAMA Neurology (2022)

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Risk-adjusted safety analysis of pacritinib (PAC) in patients (pts) with myelofibrosis (MF).
Authors: Naveen Pemmaraju, Bart L. Scott, Michael R. Savona, Stephen T. Oh, Claire Harrison, Alessandro M. Vannucchi, Francesca Palandri, Haifa Kathrin Al-Ali, Marta Sobas, Mary Frances McMullin, Vikas Gupta, Ruben A. Mesa, Sarah Buckley, Karisse Roman-Torres, Srdan Verstovsek, Abdulraheem Yacoub
Journal: Journal of Clinical Oncology (2022)

7058 Background: PAC is a novel JAK2/IRAK1 inhibitor that has shown significant activity in pts with MF, including those with platelet (plt) counts &lt;50×10 9 /L. Recently, JAK inhibitors have come under increased scrutiny due to specific, emerging toxicities with drugs in this class. This safety analysis focuses on these toxicities of interest for pts treated with PAC 200 mg BID and best available therapy (BAT), including ruxolitinib (RUX), on the Phase 3 PERSIST-2 and Phase 2 PAC203 studies. Data are presented as risk-adjusted incidences to account for differential time at risk for adverse events (AEs) between arms due to cross-over. Methods: Pts treated with PAC 200 mg BID on PERSIST-2 and PAC203, and those treated with BAT on PERSIST-2, were included. Risk-adjusted AEs, representing event rate per 100 patient-years (pt-yrs), were calculated for overall and fatal AEs, bleeding AEs (determined by Standardized Medical Dictionary for Regulatory Activities Query [SMQ]), cardiac AEs (by SMQ), major cardiac events (per major adverse cardiovascular events [MACE] classification), infections, thromboses, and secondary malignancies. Results: A total of 160 pts were analyzed as the pooled PAC group (n=106 in PERSIST-2; n=54 in PAC203) and 98 pts in the BAT group (44 on RUX). At baseline, median plt count was 57×10 9 /L; 61% had prior JAK2 inhibitor therapy. The rate of AEs was higher on PAC versus BAT, while the rate of fatal AEs was lower (Table). Both bleeding and cardiac events occurred at slightly lower rates on PAC compared to BAT. There were no MACE events on PAC, whereas there were on BAT. Malignant neoplasms occurred at similar rates on PAC and BAT, though rate of non-melanoma skin cancers was lower in pooled PAC (3/100 pt-yrs) versus BAT (7/100 pt-yrs), including RUX (11/100 pt-yrs). Infection occurred more frequently on PAC, though fungal and viral infections occurred less frequently, as did herpes zoster reactivation (pooled PAC: 0/100 pt-yrs vs BAT: 2.4/100 pt-yrs, including RUX: 5.5/100 pt-yrs). Thrombosis occurred at similar rates on PAC and BAT. Conclusions: Risk-adjusted analysis demonstrates that the safety profile of PAC 200 mg BID is comparable or superior to BAT, including RUX. PAC 200 mg BID may represent a full-dose therapeutic option for pts with MF, including those with thrombocytopenia. Clinical trial information: NCT02055781; NCT04884191. [Table: see text]
ATRT-17. A phase II study of continuous low dose panobinostat in paediatric patients with malignant rhabdoid tumours and atypical teratoid rhabdoid tumours.
Authors: Paul Wood, Jayesh Desai, Kelly Waldeck, Jason Cain, Nicholas Gottardo, Robyn Strong, Kathryn Kinross, Michelle Carr, Janelle Jones, Lily Wong, David Ziegler, Jordan Hansford, Michael Michael, David Ashley
Journal: Neuro-Oncology (2022)

Abstract BACKGROUND: Panobinostat treatment has been shown to terminally differentiate malignant rhabdoid tumours (MRT) and atypical teratoid rhabdoid tumours (ATRT) in pre-clinical models. We report results of the open label, phase II study of oral panobinostat in patients with newly diagnosed or relapsed MRT/ATRT. AIMS: To assess the anti-tumour activity of low dose, continuous oral panobinostat as well as its associated toxicities. To assess the biological activity of low dose panobinostat by measuring histone H4 acetylation status in peripheral mononuclear cells (PMNC), and differentiation markers. METHODS: Following primary institutional standard of care induction and consolidation chemotherapy and/or radiation treatment, patients were enrolled and commenced on panobinostat as a continuous daily oral dose starting at 10mg/m2/day, with a three-week wash out period between therapies. Real-time acetylation status, measuring acetylated H4 on PMNC, was performed to determine the pharmacodynamics of panobinostat at different dosing levels. Patients were monitored for toxicity; dose reductions were in decrements of 2mg/m2/day. RESULTS: A total of 13 patients with newly diagnosed ATRT/MRT and one patient with relapsed MRT have been enrolled. The average age at enrollment was 3.6 years (range 0.8-6.8 years). The mean treatment duration was 206 days (13-344 days). Currently, six patients (42.9%) remain on study with a mean study duration of 531 days (range 13-895 days). 6/14 patients (42.9%) were removed due to disease progression at a mean study duration of 245 days (44-560 days). 2/14 patients (14.3%) withdrew due to toxicity. 12/14 patients (85.7%) required dose reductions. The main toxicities were thrombocytopaenia and leukopaenia (Grade III-IV). Real-time pharmacodynamic assessment of panobinostat, at a dose as low as 6mg/m2/day resulted in significant acetylation of histone H4 in PMNC. CONCLUSIONS: Treatment with low dose panobinostat is well tolerated in infants and children with MRT/ATRT, with significant acetylation of histone H4 in PMNC.
DIPG-09. Diffuse Midline Glioma-Adaptive Combinatory Trial (DMG-ACT): A biology-driven platform trial in pediatric and young adult patients with diffuse midline glioma
Authors: Andrea Franson, Cassie Kline, Annette Molinaro, Yalan Zhang, Kelly Hitchner, Carl Koschmann, Javad Nazarian, Sabine Mueller
Journal: Neuro-Oncology (2022)

Abstract BACKGROUND: Despite advances in our understanding of the biology of diffuse midline gliomas (DMGs), little progress has been made in improving outcomes. Therapy development is limited by lack of preclinical data across multiple model systems and laboratories; limited knowledge about blood-brain barrier penetrance; and lack of multi-agent therapies. We aim to address these issues through DMG-ACT, where we translate robust preclinical data using ONC201 as the therapy backbone in a multi-arm, combination strategy within an innovative trial design. DESIGN: DMG-ACT is an open-label, multi-institutional trial of combination therapy for patients with DMG between 2 and 39 years of age. The trial utilizes a novel Bayesian drug combination platform design with adaptive shrinkage (ComPAS). ComPAS allows ongoing assessment of therapy efficacy with borrowing of data across different arms and the ability to eliminate ineffective drug combinations and add new promising combinations throughout the trial. ONC201 is the backbone therapy in each arm and given in combination with other agents that show additive or synergistic benefit in preclinical testing. Patients enter into one of three cohorts: newly diagnosed (Cohort 1), post-radiation (Cohort 2), and relapsed/progressive (Cohort 3). The cohorts offer a target validation option to assess intratumoral pharmacokinetics and pharmacodynamics of drug given prior to tumor biopsy. Cohort 1 and 3 offer radiation or re-irradiation with concomitant single agent therapy followed by maintenance combination therapy. The primary efficacy endpoints are median progression-free survival at 6 months (Cohort 1 and 2) and overall survival at 7 months (Cohort 3). Exploratory endpoints include intratumoral drug concentration, toxicity profile of combination therapy during radiation therapy, toxicity profile and efficacy of combination therapy, CSF and ctDNA analysis, and health related quality of life, cognitive, and patient/proxy-reported outcome measures. This trial was successfully launched in November 2021 with updates to be presented at the meeting.